RESUMO
Autoimmune diabetes is characterized by autoantigen-specific T cell-mediated destruction of pancreatic islet beta cells, and CD8(+) T cells are key players during this process. We assessed whether the bitransgenic RIP-CD80 x RIP-LCMV-GP (RIP-CD80GP) mice may be a versatile antigen-specific model of inducible CD8(+) T cell-mediated autoimmune diabetes. Antigen-encoding DNA, peptide-loaded dendritic cells and antigen plus incomplete Freund's adjuvant were used for vaccination. Of 14 pancreatic proteins tested by DNA vaccination, murine pre-proinsulin 2 (100% of mice; median time after vaccination, 60 days) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (77%, 58 days) could induce diabetes. Vaccination with DNA encoding for zinc transporter 8, Ia-2, Ia-2ß, glutamic acid decarboxylase 67 (Gad67), chromogranin A, insulinoma amyloid polypeptide and homeobox protein Nkx-2.2 induced diabetes development in 25-33% of mice. Vaccination with DNA encoding for Gad65, secretogranin 5, pancreas/duodenum homeobox protein 1 (Pdx1), carboxyl ester lipase, glucagon and control hepatitis B surface antigen (HBsAg) induced diabetes in <20% of mice. Diabetes induction efficiency could be increased by DNA vaccination with a vector encoding a ubiquitin-antigen fusion construct. Diabetic mice had florid T cell islet infiltration. CD8(+) T cell targets of IGRP were identified with a peptide library-based enzyme-linked immunospot assay, and diabetes could also be induced by vaccination with major histocompatibility complex (MHC) class I-restricted IGRP peptides loaded on mature dendritic cells. Vaccination with antigen plus incomplete Freund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP-CD80GP mouse. We conclude that RIP-CD80GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD8(+) T cell-targeted prevention strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Glucose-6-Fosfatase/imunologia , Insulina/imunologia , Precursores de Proteínas/imunologia , Vacinação/métodos , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Linfócitos T CD8-Positivos/metabolismo , DNA/genética , DNA/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Adjuvante de Freund/imunologia , Glucose-6-Fosfatase/genética , Glicoproteínas/genética , Glicoproteínas/imunologia , Insulina/genética , Ilhotas Pancreáticas/imunologia , Estimativa de Kaplan-Meier , Lipídeos/imunologia , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Precursores de Proteínas/genética , Ratos , Fatores de Tempo , Vacinação/efeitos adversos , Vacinas de DNA/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
How much cognitive effort does it take to change a movement plan? In previous studies, it has been shown that humans plan and represent actions in advance, but it remains unclear whether or not action planning and verbal working memory share cognitive resources. Using a novel experimental paradigm, we combined in two experiments a grasp-to-place task with a verbal working memory task. Participants planned a placing movement toward one of two target positions and subsequently encoded and maintained visually presented letters. Both experiments revealed that re-planning the intended action reduced letter recall performance; execution time, however, was not influenced by action modifications. The results of Experiment 2 suggest that the action's interference with verbal working memory arose during the planning rather than the execution phase of the movement. Together, our results strongly suggest that movement planning and verbal working memory share common cognitive resources.